Patent GB-1316312-A (GB)
Title: Tertiary aminoacids process for their manufacture and compositions  containing them
IPC: C07D211/74
Filed: 1970-07-09
Abstract: 1316312 α(p - Tertiaryaminophenyl)- akanoic acids and derivatives CIBA GEIGY AG 9 July 1970 [18 July 1969 8 Sept 1969 12 Sept 1969 3 Feb 1970 25 May 1970] 33375/70 Addition to 1268831 Heading C2C Novel compounds of Formula I in which A N- represents an unsubstituted or substituted bicyclic alkenyleneamino group with 5 or 6 members in each ring and with from 1 to 3 double bonds in the ring system, Ph represents an unsubstituted or substituted phenylene radical, R 1  represents a hydrogen atom or a lower alkyl group, and R 2  represents a hydrogen atom or a lower alkyl, lower alkenyl, unsubstituted or lower alkyl-substituted cyclealkyl, unsubstituted or lower alkyl-substituted cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyl lower alkyl group or an ester, amide, thioamide, nitrile or hydroxamic acid of such an acid, are prepared by one of the following methods: (a) a compound of Formula II wherein X 1  represents a hydrogen atom, is reacted with a compound of the formula Y 1 -C(R 1 )(R 2 )-C(=O)-OH (IIb), in which Y 1  stands for a free or reactive esterified hydroxy group, or a salt, ester, amide, thioamide, nitrile or hydroxamic acid thereof, or (b) a compound of the Formula II, in which X 1  represents a metal radical, is reacted with a compound of the formula (IIb), in which Y 1  stands for a reactive esterified hydroxy group, or a salt, ester, amide, thioamide, nitrile or hydroxamic acid thereof, or (c) a compound of the Formula II, in which X 1  represents a reactive esterified hydroxy group, is reacted with a compound of the formula Y 1 -C(R 1 )(R 2 )-C(=O)-OH (IIb), in which Y 1  stands for a metal radical, or an ester, amide, thioamide, nitrile or hydroxamic acid thereof, or (d) a compound of the Formula II, in which X 1  represents the group of the formula -C(R 1 )(R 2 )-Y 2  (IIc), in which Y 2  stands for a metal radical, is reacted with a metal-free, reactive derivative of carbonic or formic acid, or (e) a compound of the Formula II, in which X 1  represents the group of the formula (IIc), in which Y 2  stands for an unsubstituted or substituted ammonium group, is reacted with a reactive metal-containing derivative of carbonic or formic acid, or (f) a compound of the Formula II, in which X 1  represents the group of the formula -C(R 1 )(R 2 )-Y 2  (IIc), in which Y 2  stands for a free or reactive, functionally converted hydroxy group, is reacted with a reactive metal-containing derivative of carbonic or formic acid, or (g) a compound of the Formula II, in which X 1  represents the group of the formula -C(R 1 )(R 2 )-Y 2  (IIc), in which Y 2  stands for a free, esterified or salified hydroxy group, or represents a 1-lower alkenyl radical is reacted with carbon monoxide, or (h) in a compound of the Formula II, in which X 1  represents the group of the formula (IId) in which Y 3  stands for a methyl, hydroxymethyl, borylmethyl, hydroxyimino methyl, formyl, 1-lower alkenyl, 1-lower alkynyl, 1,2- dihydroxy-lower alkyl group, an acyl group or a free or functionally modified carboxy carbonyl group, Y 3  is converted into a free, esterified, amidated or thioamidated carboxyl group or a cyano group or hydroxamic acid by oxidation or rearrangement, or (i) in a compound of the Formula II, in which X 1  represents the group of the formula -C(R 1 )(R 2 )-Y 3 , in which Y 3  stands for a free or esterified carboxycarbonyl group, Y 3  is converted into a free or esterified carboxy group by oxidation or decarbonylation, or (j) a compound of the Formula II, in which X 1  represents a group of the formula -C(R 1  or R 2 ) (Y 4 )-C(=O)-OH (IIf) or of the formula -C(=Y 5 )-C(=O)-OH (IIg), in which Y 4  represents a free or reactive esterified or etherified hydroxy or free or reactive esterified or etherified mercapto group, and Y 6  represents a lower alkylidene, cycloalkylidene or cycloalkyl-lower alkylidene group or an oxo group or a free or ketalized thio group, or a corresponding ester, amide, thioamide or nitrile or a corresponding quaternary ortho or para-quinone methide of such compound is treated with catalytically activated or electrolytically generated hydrogen or with a chemical reducing agent, if desired, in the presence of a desulphurizing agent, or (k) a compound of the Formula II, in which X 1  represents the group of the formula -C(R 1  or R 2 ) (Y 4 )-C(=O)-OH (IIf), in which Y 4  represents a carboxy group, or an ester, amide, thioamide, nitrile or hydroxamic acid thereof is decarboxylated by pyrolysis, or (1) a compound of the Formula II, in which X 1  represents a group of the formula -C(R 1  or R 2 ) (Y 4 )-C( = O)-OH (IIf), in which Y 4  represents an acyl group, or an ester, amide, thioamide, nitrile or hydroxamic acid is subjected to #- keto-acid splitting by treatment with a strongly alkaline agent, or (m) a compound of the Formula II, in which X 1  represents an acetyl group, is treated with sulphur in the presence of ammonia or a primary or secondary amine, or (n) a compound of the Formula II, in which X 1  represents a group of the formula (IIh) is subjected to hydrolysis, alcoholysis, ammonolysis or aminolysis, (o) a compound of the Formula II, in which X 1  represents a group of the formula -C(=O)-C(R 1 )(R 2 )-Hal (IIi), in which Hal stands for a halogen atom, is treated with a strongly alkaline agent or with a soluble silver salt, or (p) a compound of the Formula III or an ester, amide, thioamide, nitrile or hydroxamic acid thereof, is reacted with a compound of the formula A N-Y 6  (IIIa), one of the radicals X 2  and Y 6  representing a hydrogen atom or a metal group and the other a free or reactive esterified hydroxy group, or (q) a compound of the Formula III or an ester, an amide, a thioamide, nitrile or hydroxamic acid thereof, in which X 2  represents a primary, secondary or tertiary amino group, is reacted with an amine of the formula A N-H, or (r) a compound of the Formula III, in which X 2  represents a primary amino group, or an ester, amide, thioamide, nitrile or hydroxamic acid thereof, is reacted with a compound of the formula HO-A-OH (IIIb) or with a reactive derivative thereof or with a corresponding dehydrated compound thereof, or (s) a compound of the Formula III, in which X 2  represents a radical of the formula A 0  N- which stands for a bicyclic alkyleneamino group having 5 or 6 ring members in each ring, and which group contains one or more of the same or different substituents selected from hydroxy, mercapto, amino, ammonium, hydrazino and hydrazono groups and functionally converted groups corresponding to these or an ester, amide, thioamide, nitrile or hydroxamic acid thereof, is dehydrated, dehydrosulphidated, deaminated or pyrolysed, a resulting compound is converted within the scope defined into another compound of this invention, and/or, if desired, a resulting free compound is converted into a salt or a resulting salt into a free compound, and/or, if desired, a resulting mixture of isomers is resolved into the individual isomers. Examples relate to α[4-(2- isoindolin - yl) - phenyl]acetic or propionic acids and their ethyl esters, α-[4-(2-isoindolinyl)- 3 - chlorophenyl] propionic acid and its ethyl ester, ethyl α - [4- (1,3 - dioxo - 1,2,3,4 - tetrahydro - 2 - isoquinolinyl) - phenyl] - acetate ethyl α - [3 - chloro - 4 - (1,3 - dioxo - 2 - isoindolinyl) - phenyl] - propionate and α[ - 3- chloro - 4 - (1 - oxo - 2 - isoindolinyl) - phenyl]- propionic acid and its ethyl ester. Intermediates prepared are ethyl 4-aminophenyl acetate ethyl α-(4-nitrophenyl)-propionate, ethyl α - (4 - aminophenyl) - propionate, ethyl α - (4 - acetamidophenyl) - propionate, ethyl α- (3 - chloro - 4 - acetamidophenyl) - propionate, ethyl α - (4 - amino - 3 - chlorophenyl) - propionate, ethyl α - (4 - acetamidophenyl) - acetate, diethyl α - (3 - chloro - 4 - nitrophenyl) - α - methylmalonate and diethyl α - (3 - chloro - 4 - aminophenyl) - α -methyl-malonate. Pharmaceutical compositions in conventional forms for enteral, parenteral or topical administration and having anti-inflammatory analgesic and antifungal activity comprise an above novel compound and a carrier or diluent.